The present invention is related to the prolonged release of an active agent from a dosage form. More particularly, it relates to a multilayered active agent dosage form having a highly swellable layer and a drug layer, the dosage form being adapted for retention in the stomach for a prolonged period.
Controlled release dosage forms that provide for prolonged delivery of active agent formulations to the environment of use have found application for increasing numbers of active agents. However, with respect to pharmaceutical and veterinary active agent formulations, there has been a need not only to provide for prolonged delivery of the active agent over time, but also to provide prolonged delivery of the active agent at a particular location or locations in the environment of use, such as in the stomach.
Certain active agents are absorbed primarily from the small intestine. Generally, the time of passage of different particles through the small intestine does not vary significantly, and passage is generally independent of food intake and particle size. Thus, active agent dissolved in liquid, solid active agent dispersed in liquid and relatively larger delivery units of active agent, such as microcapsules and the like, will traverse the length of the small intestine in substantially the same time frame, usually about 3-5 hours. For active agents that are not easily absorbed by the small intestine or that do not dissolve readily, the window for active agent absorption in the small intestine may be too short to provide a desired therapeutic effect. This fact often creates a need for frequent dosing of active agent in order to provide and maintain adequate levels of active agent in blood plasma. The need for frequent dosing presents compliance problems and is often inconvenient for the user as well.
Since it has been found difficult to alter the transit time of active agent through the small intestine, some emphasis has been placed on attempting to control the transit time of active agents in the stomach. Most active agents are not well absorbed in the stomach, but even in those instances where the active agent is not well absorbed, the continuous release of active agent in the stomach over a prolonged time period will dispense active agent over that same period of time to the small intestine where it can be absorbed.
The physiological behavior of the stomach is usually determined by whether it contains food or is empty. Food is mixed and partially digested in the distal stomach (antrum). As the stomach undergoes contractions, partially digested material is discharged into the small intestine and non-digested material is retropelled into the main part of the stomach for further digestion. In the fed state, non-digested material is not generally able to leave the stomach. At the end of a digestive period, the stomach enters the fasting stage and begins a cycle called the interdigestive myoelectric motor cycle or IMMC.
The IMMC can be considered to be divided into four phases: (1) phase 1 is an approximately one hour period with no contractions; (2) phase 2 is about a forty minute period of intermittent potentials and contractions that increase in intensity over time; (3) phase 3 is a relatively short period, generally between about five to fifteen minutes, of intense contractions (commonly called the xe2x80x9chousekeeper wavexe2x80x9d) that completely empties the stomach; and (4) phase 4 is a short transitory period between the intense activity of phase 3 and the quiescence of phase 1. The different phases move distally from the stomach to the terminal ileum over an approximately two hour period as the cycle is repeated. Since the cycle is interrupted by the receipt of food by the stomach, it is possible to delay the emptying phase, phase 3, by maintaining a fed state. However, it is not practical to regularly maintain the fed state over a long period of time. Consequently, a need exists for a delivery device that can remain in the stomach for a significant period, whether in the fed or fasted state, and deliver active agent to the stomach over a prolonged period of time.
A variety of studies have been conducted in dog and in man to determine sizes of objects that would be retained in the stomach during the fed stage and also in the fasting stage when IMMC is present. Khosla and Davis, International Journal of Pharmaceutics, Vol. 62 (1990), pages R9-R11 have reported that a particle size less that 2 mm generally results in emptying from the stomach of the dog. Non-disintegrating tablets having sizes of 7, 11 and 13 mm in diameter were emptied from the human stomach, but the larger sized tablets tended to remain in the stomach longer than the small sized tablets. Tablets larger than 11 mm tended to be emptied only during the IMMC. Davis et al., Pharmaceutical Research, Vol. 8, No. 10 (1991) has described retention of radio-telemetry capsules having a size of 25xc3x978 mm in the stomach of human subjects past phase 3 of the IMMC. Timmermans et al., Journal of Pharmaceutical Sciences, Vol. 82, No. 8 (1993) has reported the mean resting pyloric diameter in humans as 12.8xc2x17.0 mm. Accordingly, it is important that gastric retentive delivery vehicles are adapted to disintegrate, dissolve or erode to sizes that permit eventual elimination of the vehicle without causing gastric obstruction.
Various attempts to provide active agent delivery devices that remain in the stomach for extended periods or time have been described previously. For example, U.S. Pat. No. 4,851,232 describes a hydrogel reservoir containing tiny pills having a active agent core surrounded by a wall controlling delivery of active agent to the stomach. The hydrogel swells in the stomach to facilitate retention of the active agent reservoir in the stomach over time.
U.S. Pat. No.4,871,548 describes a dosage form including a mixture of low and high number average molecular weight hydroxypropylmethylcellulose polymers and active agent that swells when in the stomach.
U.S. Pat. No. 4,767,627 describes substantially planar devices formed of bioerodible polymer including active agent that may be compressed and folded for oral administration and then released and unfolded in the stomach, where the devices are to be retained over an extended period of time. The devices have a longest diameter of between 1.6 and 5 cm. It is suggested that as an alternative to incorporating the active agent into the device a controlled release active agent module, mechanically or osmotically driven, can be glued or tethered to the device.
U.S. Pat. No. 5,443,843 describes a plurality of compressible retention arms and an attached controlled release device which in the expanded form resists gastrointestinal transit. The system can have a collar or a belt for receiving and holding a active agent-containing, orally-administrable controlled release device. In a fully expanded configuration for human use, the system is described as having minimum and maximum dimensions of 2.5 and 6.0 centimeters, respectively.
U.S. Pat. No. 5,007,790 describes a sustained release active agent dosage form in the form of a capsule or tablet that includes a plurality of hydrophilic water-swellable, cross-linked polymer particles that swell in the stomach to promote gastric retention and permit gastric fluid to penetrate the particles to dissolve active agent and deliver it to the stomach in the solution state. The particles are indicated to retain their physical integrity over the dosing period. Initially sized particles, indicated to be preferably spherical, are disclosed to be in the range of 50 xcexcm to 2 mm, swell to a size of about 3 mm. A plurality of particles are packed into a capsule for administration to a patient.
U.S. Pat. No. 5,582,837 describes a dosage form similar to that of U.S. Pat. No. 5,007,790, without the use of a cross-linked hydrophilic polymer. The particles are described as slippery and soft, preferably spherical, and having dimensions on the order of 6 to 18 mm in the swollen state. The particles can be packed into capsules containing 7-25 spherical particles, depending on the size, or formulated into tablets that contain from 2-25 spherical particles.
The use of albumin-cross-linked polyvinylpyrrolidone hydrogels to deliver flavin mononucleotide to dogs has been described by Park et al. in Journal of Controlled Release, Vol.19 (1992) pages 131-134. The hydrogels were maintained in the stomachs of dogs for extended periods, even in the fasted state. Gels with a glassy core tended to remain in the stomach longer than hydrogels without the glassy core. Control of the size of the core was attempted by administration of water in the stomach. While it is possible to control the dimensions of the hydrogel in the dry state, controlling the size of the glassy core within the hydrogel after administration to a subject by addition of water is not suitable for fabrication of a dosage form that can routinely and controllably be retained in the stomach of a subject over a prolonged period of time.
While it is important that the delivery device be adapted to remain in the stomach for a prolonged period, it is also important that the device deliver active agent in a controlled manner. Even though control over the delivery of active agents that are released from a highly swellable matrix as described in International Application WO 99/07342, published Feb. 18, 1999, may be achieved in many instances, a greater degree of control is possible when the retention function of the dosage form and the drug delivery function of the dosage form are addressed individually.
Delivery systems, such as those described below, are representative of the many different systems have been suggested for controlled delivery of active agents from a dosage form over a prolonged period of time with no particular emphasis on retention of the dosage form in the stomach for a prolonged period.
For example, U.S. Pat. No. 4,290,426 to Lusted et al describes a cylindrical dispenser for releasing a beneficial agent into a fluid environment at a rate that is governed by the fluid induced relaxation of a polymeric agent contained within the dispenser. The cylindrical dispenser includes an impermeable container that has within it a reservoir and a passageway from the reservoir to the exterior of the container. The reservoir contains a polymer and a beneficial agent. The polymer imbibes fluid from the environment and thereby undergoes relaxation, releasing the beneficial agent from the device. The amount of agent released is dependent on the rate of relaxation of the polymer over time.
Coated dosage forms have also been suggested for delivery of a controlled amount of a beneficial agent over a prolonged period of time. U.S. Pat. No. 5,256,440 describes a process for producing a film coated dosage form. A continuous groove is inscribed in a dosage form core. A latex film is coated onto the core, the groove defining a fixed zone and a detachable zone for the film. The detachable portion of the latex film detaches when it is exposed to the environment of use, thereby exposing a discrete portion of the dosage form core surface. The remainder of the film remains attached to the dosage form core. The exposed portion of the dosage form surface erodes and releases active agent to the environment of use.
Coated tablets for constant and prolonged active agent release are described by Conte et al in J. Controlled Release, Vol. 26, (1993) pages 39-47. These GEOMATRIX(trademark) Systems are swellable matrices that are coated or tableted with polymeric barrier layers. Release performances of the systems are modulated as a result of the reduction of the releasing surface exposed to the dissolution medium by the polymeric barrier layer coatings. As the extent of coating of the system""s surface is increased, the release kinetics of the system shift toward constant release. These systems are further described in U.S. Pat. No. 4,839,177 to Colombo et al.
U.S. Pat. No. 5,780,057 describes a two or three layered tablet where at least one of the layers swells by contact with biological fluids to promote retention of the tablet in the stomach where the active ingredient may be slowly released. The description indicates that at least one of the layers acts as a barrier for a predetermined period of time to the active agent that is contained one of the other layers.
U.S. Pat. No. 5,534,263, which is incorporated herein by reference, describes a dosage form useful for the prolonged delivery of an active agent formulation in the form of a matrix having two or more insoluble bands on the surface of the matrix. The exposed surfaces of the matrix erode in a manner that creates additional surface areas to provide for prolonged release of an active agent formulation with determined release profiles. That patent is not concerned with dosage forms that are retained in the stomach for a prolonged period of time.
Additional oral, controlled-release dosage forms include elementary osmotic pumps, such as those described in U.S. Pat. No. 3,845,770, mini-osmotic pumps such as those described in U.S. Pat. Nos. 3,995,631, 4,034,756 and 4,111,202, and multi-chamber osmotic systems referred to as push-pull, push-melt and push-stick osmotic pumps, such as those described in U.S. Pat. Nos. 4,320,759, 4,327,725, 4,449,983, 4,765,989, 4,892,778, 4,940,465, 4,915,949 and 5,126,142, all of which are incorporated herein by reference.
Administration of acyclovir by sipped solution over a four-hour period has been described in Br. J. clin. Pharmac., 21, 459-462 (1986) to achieve an increased contact time with the human stomach and the gastrointestinal tract. The total amount of acyclovir absorbed was increased over that observed with administration of acyclovir tablets. However, continuous oral administration requiring the interaction of the patient is not what would generally be considered suitable therapy. The influence of food on gastric retention time and the absorption of acyclovir has been reported in International Journal of Pharmaceutics, Vol. 38 (1987), pages 221-225. As reported there, compared to a lighter meal, the heavier meal slowed the rate of gastric emptying, prolonged small intestinal transit time and decreased absorption of the active agent.
As can be observed in the above-referenced patents and publications, devices have been described that provide for prolonged delivery of an active agent and retention in the gastric environment. However, there remains a continuing need for improved systems for delivering an active agent to the gastric environment over a prolonged period of time and in a reliable, controllable and reproducible manner.
In one aspect, the invention comprises an active agent dosage form adapted for gastric retention comprising (a) a first layer comprising a swellable, water-soluble polymer, (b) a second layer comprising a therapeutically-effective amount of an active agent, the second layer being laminated with the first layer at a common surface, and (c) at least one band of insoluble material circumscribing and binding together the first layer and the second layer, the first layer being adapted to swell in the stomach to facilitate retention of the dosage form in the stomach over a prolonged period of time. Preferably, the release of the active agent from the second layer is independent of the composition of the first layer and occurs over a prolonged period of time. Examples of water soluble polymers include polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, maltodextrin, pre-gelatinized starch, guar gum, sodium alginate, or polyvinyl alcohol, and most preferably high molecular weight polyethylene oxide, e.g., Polyox(copyright) brand of polyethylene oxide (Union Carbide Corporation, Danbury, Conn.). The first layer preferably swells more rapidly and to a greater extent than does the second layer. The first layer may be gel-like and exhibit a slippery external surface.
In another aspect, the first or second layers of the above-described dosage form comprises a hydroattractant selected from low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid, cross-linked Amberlite resin, alginates, colloidal magnesium-aluminum silicate, corn starch granules, rice starch granules, potato starch granules, pregelatinized starch, sodium starch glycolates, guar gum, soybean fiber, psyllium husk fiber, rice husk fiber, wheat fiber, alginic acid derivatives such as sodium alginate and alginic acid, silicates such as bentonite, colloidal magnesium and aluminum silicate (Veegum), gelatin, cross-linked gelatin, sodium carboxymethyl starch, sugars and sodium chloride.
In another aspect, the invention comprises the dosage form as described above wherein the weight percent of the water soluble polymer in the first layer is about 5 to 100 weight percent and weight percent of the hydroattractant in the first layer is about 0 to 60 weight percent, and the weight percent of the water soluble polymer in the second layer is about 5 to 95 weight percent and the weight percent of the hydroattractant is about 5 to 70 weight percent. The dosage form of the invention releases the active agent over a prolonged period time of at least about 3 hours, more often between 8 to 12 hours.
In still another aspect, the second layer may be formed of a plurality of sublayers, each containing differing amounts of active agent or different active agent or each being of different thickness to provide active agent release profiles that vary with time.
In a further aspect, the invention comprises a method of treating a subject in need thereof with an active agent that comprises administering to the subject a multilayered dosage form adapted to be retained in the stomach over a prolonged period of time, the dosage form comprising a first layer adapted to swell in the stomach of the subject and retain the dosage form in the stomach for a prolonged period of time, and a second layer adapted to deliver to the subject an active agent at a variable rate of delivery. The second layer may be comprised of multiple laminates, each having a different active agent concentration per unit volume and/or different thickness. The method may comprise administering one or more dosage forms to the subject in the fed state at the start of each dosing period, such as within one hour of the subject consuming food.